Inhibitor of cyclooxygenase-2 induces cell-cycle arrest in the epithelial cancer cell line via up-regulation of cyclin dependent kinase inhibitor p21

Abstract

Cyclooxygenase-2 is the rate-limiting enzyme in synthesis of prostaglandins and other eicosanoids. Prior reports have shown that inhibition of cyclooxygenase-2 activity, either by selective inhibitors or by antisense oligonucleotide, results in suppression of growth of squamous cell carcinoma cell lines which express high cyclooxygenase-2 levels, such as NA, a cell line established from a squamous cell carcinoma of the tongue. To investigate the mechanisms by which cyclooxygenase-2 inhibitors suppressed growth of these cells, the effects of NS-398, the selective cyclooxygenase-2 inhibitor, on cell-cycle distribution were examined. NS-398 induced G0/G1 cell-cycle arrest in NA cells which expressed cyclooxygenase-2. G0/G1 arrest induced by NS-398 was accompanied by up-regulation of cyclin-dependent kinase inhibitor p21, but not by up-regulation of the other cyclin-dependent kinase inhibitors. Transfection with p21 antisense oligonucleotide inhibited cell-cycle arrest induced by NS-398. Accumulation in G0/G1 was also observed in NA cells transfected with cyclooxygenase-2 antisense oligonucleotide. On the other hand, NS-398-treated NA cells showed a loss of plasma membrane asymmetry, a marker of early events in apoptosis. However, NS-398 did not induce other morphological and biochemical changes related to apoptotic cell death. These results suggest that cyclooxygenase-2 inhibitor induces G0/G1 cell-cycle arrest in NA cells by upregulation of p21. Our results also suggest that NS-398 is not sufficient to complete the whole process of apoptosis in NA cells, although it induces an early event in apoptosis.

Overexpression of COX-2 gene in oral cancer is independent of stage of disease and degree of differentiation

“…Selective COX-2 inhibitors suppress growth of cells by inducing G0/G1, cell-cycle arrest and thus apoptosis 40 .…”

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

“…Another large population-based survey reported that the use of NSAIDs significantly reduced the risk of both gastric and oesophageal carcinoma (Farrow et al, 1998). Although the precise mechanisms by which NSAIDs, and COX-2 selective inhibitors in particular, modulate tumour growth have not been elucidated, it appears that cell cycle arrest and apoptosis may play a critical role (Chang and Weng, 2001;Grosch et al, 2001;Cheng et al, 2002;Joe et al, 2002;Kundu et al, 2002;Toyoshima et al, 2002). Alternatively, Sawaoka et al (1998) and Tsujii et al (Tsujii and DuBois, 1995;Sawaoka et al, 1998;Tsujii et al, 1998) have suggested that a decrease in angiogenesis may account for the inhibitory properties of COX-2 selective NSAIDs on tumour growth.…”

microRNA expression pattern and its alteration following celecoxib intervention in human colorectal cancer

“…Celecoxib, an inhibitor of cyclooxygenase-2 (COX-2), may prevent CRC, and even prohibits the growth of tumor cells, through the inhibition of angiogenesis, apoptosis and blockage of the cell cycle (13)(14)(15). However, to date, its exact anti-cancer mechanism in malignant neoplasms, including CRC, is poorly understood.…”